Therapeutic implication of chimeric antigen receptor T-cell therapy for head and neck squamous cell carcinoma
Authors: Jayanthi Pazhani, Selvaraj Jayaraman, Vishnu Priya Veeraraghavan
Journal: International Journal of Surgery (2023)

Dear Editor, Oral squamous cell carcinoma is the major histopathological type of head and neck carcinoma, which is the world's sixth most common cancer. Surgery, radiation therapy, and chemotherapy are the mainstay of treatment options in patients with head and neck squamous cell carcinoma (HNSCC). Despite advances in therapy, the 5-year survival rate of patients ranges between 25 and 55%1. Alternative therapeutic strategies that could improve the outcome of the patients are required and are constantly under research. Immunotherapy, such as inhibitors of immune checkpoints and adoptive cellular therapy (ACT) have revolutionized the management of hematological malignancies. However, the use of ACT in solid malignancies including HNSCC is still in its early stages2. In ACT, a patient's T cells are removed and then modified in the laboratory. These modified T cells are later reinfused back to the patient. ACT results in T-cell proliferation and persistence, thus providing the advantage of increased specificity and reactivity of T cells against the tumor tissue. Three forms of ACTs are currently in use: chimeric antigen receptor (CAR) T cells, genetically modified T-cell receptors (TCRs), and tumor-infiltrating lymphocytes. In tumor-infiltrating lymphocyte therapy, a heterogeneous group of T cells in the tumor are expanded, whereas, TCRs and CAR T cells are characterized by the expansion of genetically altered T cells that are directed against specific antigens. The major difference between CAR T-cell therapy and TCR is that the cell surface antigens are recognized by CAR T cells independent of human leukocyte antigen presentation3. The structure of CARs consists of four major parts as shown in Figure 1. (i) An extracellular antigen binding region that recognizes specific tumor antigens without a major histocompatibility complex, (ii) a transmembrane domain, (iii) an intracellular signaling domain, and (iv) an extracellular hinge domain. A single chain variable fragment derived from a tumor-specific antibody is present in the extracellular region that helps the T cell in binding to the tumor antigen. The intracellular signaling domain consists of CD3ζ immunoreceptor tyrosine-based activation motif component which initiates the T-cell activation. The extracellular single chain variable fragment and intracellular CD3ζ immunoreceptor tyrosine-based activation motif components are bridged together via the transmembrane domain using co-stimulatory molecules, such as CD28, CD27, or OX404. Initial studies have used CARs with intracellular signaling domains composed of only CD3ζ for T-cell activation. With limited antitumor activity in vivo. Hence, subsequent generations of CAR T cells were produced that included co-stimulatory molecules in their intracellular domains5.Figure 1: CAR T cells have an extracellular domain with scFv component that recognizes the target antigen independent of MHC. The transmembrane domain connects the extracellular component to an intracellular signaling domain composed of co-stimulatory molecules, which triggers the downstream T-cell activation. In contrast, TCRs are heterodimers consisting of α and β subunit that recognizes intracellular antigen presented by MHC. CAR, chimeric antigen receptor; MHC, major histocompatibility complex; scFv, single chain variable fragment, TCR, T-cell receptor.CAR T-cell therapy that was originally approved by the Food and Drug Administration (FDA) for treating high-grade lymphoproliferative malignancies, such as large B-cell lymphoma and acute lymphoblastic leukemia had specificity for CD192. A study done by Brown et al.6 showed complete regression of multifocal glioblastoma multiforme in a patient following the use of intracranial CAR T cells directed against interleukin-13 receptor α2. Adusumulli and colleagues administered mesothelin-specific CAR T cells intrapleurally followed by inhibitors of immune checkpoints. This combination therapy was tested in 14 patients with malignant pleural mesothelioma, out of which two showed complete response and five patients had partial response7. A phase I trial by Specht et al.8 using CAR T cells directed against a tyrosine kinase receptor called ROR1, demonstrated a decreased disease burden in four out of five patients with breast and lung cancers. Haist and colleagues designed a new cetuximab CAR construct and expressed these CARs on human T cells. Cetuximab is a monoclonal antibody that recognizes domain III of the epidermal growth factor receptor. The authors demonstrated that HNSCCs showing positive expression of epidermal growth factor receptor reacted to cetuximab CAR construct expressed on T cells9. Although multiple trials are ongoing, the effectiveness of CAR T cells is limited in the management of solid tumors, since a target antigen may not always exist for majority of these tumors. Furthermore, the current generation of CAR T cells have decreased antigen sensitivity, resulting in acquired resistance to this therapy. The tumor-associated antigen heterogeneity is a major problem in the development of CAR T cells against HNSCC. This drawback can be overcome using 'T cells redirected for antigen-unrestricted cytokine-initiated killing (TRUCK).' These current fourth-generation CAR T-cell products rely on cytokine-mediated destruction of T cells. A CAR T-cell targeted against a specific antigen is combined with the release of a cytokine on activation, thereby resulting in the destruction of regulatory T cells9. Mei and colleagues constructed a second-generation CAR targeting MUC1, a protein belonging to the mucin family, and tested the cytotoxic function against HNSCC cell lines in vitro. They also constructed a fourth-generation CAR that secrets interleukin-22 and verified the antitumor function of these two different CAR T cells in vivo and in vitro, respectively. The results showed that CAR-MUC1-IL22 T cells produced an effective cytotoxic function against MUC1-positive HNSCC cells in vivo10. In future, CAR T-cell adoptive therapy will likely include strategies such as TRUCK that uses cytokine-mediated killing and various other multitarget approaches. These combination therapies are aimed to overcome tumor-associated antigen heterogeneity and the inhibitory microenvironment of the supporting stroma in solid tumors. A thorough understanding of the various tumor antigens, their microenvironment, and the resistance mechanisms will not only help to improve the outcome of patients with HNSCC but will also provide a platform for further researches to overcome the limitations associated with CAR T-cell therapy. Ethical approval Not applicale. Sources of funding None. Authors' contribution S.J. and V.P.V.: conceptualization, writing – reviewing and editing. J.P.: writing – original draft preparation. S.J.: visualization and supervision. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) None. Guarantor Selvaraj Jayaraman and Vishnu Priya Veeraraghavan.